化疗是结直肠癌(CRC)的主要治疗方式之一。而化疗耐药是导致疗效不佳、患者肿瘤复发的主要原因。我们前期发现hnRNP L可与DNA结合并调节DNA修复（Hu, 2015. PNAS）；沉默hnRNP L可提高CRC细胞对5-氟尿嘧啶（5-FU）以及奥沙利铂（Oxaliplatin）的敏感性。由此，我们提出hnRNP L介导化疗耐药的新机制，即hnRNP L通过促进DNA修复，去除5-FU代谢产物及Oxaliplatin对DNA的损伤，避免自身凋亡。本项目拟进一步采用免疫共沉淀、蛋白质谱分析以及siRNA等手段揭示hnRNP L在5-FU及Oxaliplatin耐药中的作用，并观察hnRNP L缺失对肿瘤耐药细胞的生物学行为影响，旨在探索hnRNP L调控下DNA修复介导耐药的机制，以及干预hnRNP L作为治疗CRC耐药的可行性等关键科学问题。为降低化疗抵抗，制定合理的治疗方案提供新思路。

Chemotherapy resistance is an intractable problem during the treatment of colorectal cancer(CRC). In previous work, we firstly figure out hnRNP L could regulate DNA repair process directly. Knockdown of hnRNP L could enhance the chemotherapeutic response of CRC cells to 5-fluorouracil(5-FU) and Oxaliplatin. So we hypothesize the mechanism of chemotherapy resistance induced by hnRNP L, that it can eliminate DNA damage cause by the metabolites of 5-FU and Oxaliplatin through promoting DNA repair, resulting cell apoptosis escape. In this project we will find out the functions of hnRNP L during the chemotherapy resistance and watch the impact of defecting hnRNP L on CRC cells during chemotherapy by utilize techniques such as immunoprecipitation, mass spectrometer analysis and siRNA knockdown, etc. This project has important scientific significance in revealing the molecular mechanisms of inhibiting DNA repair by hnRNP L inactivation and evaluating the clinical feasibility of hnRNP L in chemotherapy resistance. Besides, it provides clinical novel ideas for making more reasonable therapeutic strategies in future.